The DYT6 Dystonia Protein THAP1 Regulates Myelination within the Oligodendrocyte Lineage

Yellajoshyula, Dhananjay; Liang, Chun Chi; Pappas, Samuel S.; Penati, Silvia; Yang, Angela; Mecano, Rodan; Kumaran, R. Ileng; Jou, Stephanie; Cookson, Mark; Dauer, William T.

doi:10.1016/j.devcel.2017.06.009

Cited by 51 publications

(92 citation statements)

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“…Thap1 C54Y/؉ mice display a striatal hypercholinergic state and dopamine D2R-induced paradoxical excitation of striatal cholinergic interneurons Thap1 C54Y/ϩ mice are a heterozygous knock-in model with a mutation in Thap1 that is known to be a cause of human isolated dystonia (Bressman et al, 2009;Djarmati et al, 2009;Fuchs et al, 2009;Blanchard et al, 2011;Lohmann et al, 2012;Ruiz et al, 2015;Yellajoshyula et al, 2017). In the Thap1 C54Y/ϩ line, basal extracellular striatal acetylcholine levels varied by sex and genotype ( Fig.…”

Section: Resultsmentioning

confidence: 97%

“…Recently, additional genetic mouse models of dystonia have become available. DYT6 is caused by heterozygous mutations in the gene for the transcription factor THAP1 (Bressman et al, 2009;Djarmati et al, 2009;Fuchs et al, 2009;Ruiz et al, 2015;Yellajoshyula et al, 2017) and DYT25 is caused by mutations of the gene for G␣ olf (GNAL), a G-protein signaling molecule downstream of striatal dopamine D1 rceptors (D1Rs) and adenosine A2A receptors (A2ARs) (Bressman et al, 1994;Belluscio et al, 1998;Fuchs et al, 2013;Pelosi et al, 2017). In patients, both DYT6 and DYT25 share some features with DYT1: they are isolated dystonias, they exhibit incomplete penetrance, and none of them respond very well to currently available therapies.…”

Section: Introductionmentioning

confidence: 99%

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Diverse Mechanisms Lead to Common Dysfunction of Striatal Cholinergic Interneurons in Distinct Genetic Mouse Models of Dystonia

Jaunarajs¹,

Scarduzio²,

Ehrlich

et al. 2019

J. Neurosci.

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Clinical and experimental data indicate striatal cholinergic dysfunction in dystonia, a movement disorder typically resulting in twisted postures via abnormal muscle contraction. Three forms of isolated human dystonia result from mutations in the TOR1A (DYT1), THAP1 (DYT6), and GNAL (DYT25) genes. Experimental models carrying these mutations facilitate identification of possible shared cellular mechanisms. Recently, we reported elevated extracellular striatal acetylcholine by in vivo microdialysis and paradoxical excitation of cholinergic interneurons (ChIs) by dopamine D2 receptor (D2R) agonism using ex vivo slice electrophysiology in Dyt1 ⌬ GAG/ϩ mice. The paradoxical excitation was caused by overactive muscarinic receptors (mAChRs), leading to a switch in D2R coupling from canonical G i/o to noncanonical ␤-arrestin signaling. We sought to determine whether these mechanisms in Dyt1 ⌬ GAG/ϩ mice are shared with Thap1 C54Y/ϩ knock-in and Gnal ϩ/ Ϫ knockout dystonia models and to determine the impact of sex. We found Thap1 C54Y/ϩ mice of both sexes have elevated extracellular striatal acetylcholine and D2R-induced paradoxical ChI excitation, which was reversed by mAChR inhibition. Elevated extracellular acetylcholine was absent in male and female Gnal ϩ/ Ϫ mice, but the paradoxical D2R-mediated ChI excitation was retained and only reversed by inhibition of adenosine A2ARs. The G i/o-preferring D2R agonist failed to increase ChI excitability, suggesting a possible switch in coupling of D2Rs to ␤-arrestin, as seen previously in a DYT1 model. These data show that, whereas elevated extracellular acetylcholine levels are not always detected across these genetic models of human dystonia, the D2Rmediated paradoxical excitation of ChIs is shared and is caused by altered function of distinct G-protein-coupled receptors.

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Section: Resultsmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

Diverse Mechanisms Lead to Common Dysfunction of Striatal Cholinergic Interneurons in Distinct Genetic Mouse Models of Dystonia

Jaunarajs¹,

Scarduzio²,

Ehrlich

et al. 2019

J. Neurosci.

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“…In mouse brain, THAP1 mutations or deletions lead to dysregulation of genes involved in pathways of eIF2α signaling, mitochondrial dysfunction, and neuron projection development (Zakirova et al 2018). Another study found that THAP1 is required for the timing of myelination initiation in oligodendrocyte during CNS maturation in mouse (Yellajoshyula et al 2017). More recently, Frederick et al (2019) transmission, cytoskeleton, gliosis, and dopamine signaling.…”

Section: Discussionmentioning

confidence: 99%

“…The THAP1 protein belongs to the family of zinc fingercontaining transcription factor and functions as a transcription factor (Roussigne et al 2003;Bessière et al 2008). Recently, comprehensive transcriptome analysis of mouse model for DYT6 dystonia showed altered expression of genes involved in many different pathways (Yellajoshyula et al 2017;Zakirova et al 2018;Frederick et al 2019). However, the transcriptional functions of THAP1 in human neuronal cells are still unclear.…”

Section: Introductionmentioning

confidence: 99%

Unraveling Molecular Mechanisms of THAP1 Missense Mutations in DYT6 Dystonia

et al. 2020

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Mutations in THAP1 (THAP domain-containing apoptosis-associated protein 1) are responsible for DYT6 dystonia. Until now, more than eighty different mutations in THAP1 gene have been found in patients with primary dystonia, and two third of them are missense mutations. The potential pathogeneses of these missense mutations in human are largely elusive. In the present study, we generated stable transfected human neuronal cell lines expressing wild-type or mutated THAP1 proteins found in DYT6 patients. Transcriptional profiling using microarrays revealed a set of 28 common genes dysregulated in two mutated THAP1 (S21T and F81L) overexpression cell lines suggesting a common mechanism of these mutations. ChIP-seq showed that THAP1 can bind to the promoter of one of these genes, superoxide dismutase 2 (SOD2). Overexpression of THAP1 in SK-N-AS cells resulted in increased SOD2 protein expression, whereas fibroblasts from THAP1 patients have less SOD2 expression, which indicates that SOD2 is a direct target gene of THAP1. In addition, we show that some THAP1 mutations (C54Y and F81L) decrease the protein stability which might also be responsible for altered transcription regulation due to dosage insufficiency. Taking together, the current study showed different potential pathogenic mechanisms of THAP1 mutations which lead to the same consequence of DYT6 dystonia.

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“…qCHIP was performed as previously described (Yellajoshyula et al, 2017) with minor modifications. A pool of isolated cerebellum tissue from P14 mice (three to six mice per genotype) was digested for 20 minutes with Pappain (SKU no.…”

Section: Fast Chromatin Immunoprecipitation (Qchip)mentioning

confidence: 99%

Altered Capicua expression drives regional Purkinje neuron vulnerability through ion channel gene dysregulation in Spinocerebellar ataxia type 1

Chopra

Bushart

Cooper

et al. 2020

Preprint

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Selective neuronal vulnerability in neurodegenerative disease is poorly understood. Using the ATXN1[82Q] model of spinocerebellar ataxia type 1 (SCA1), we explored the hypothesis that regional differences in Purkinje neuron degeneration could provide novel insights into selective vulnerability. ATXN1[82Q] Purkinje neurons from the anterior cerebellum were found to degenerate earlier than those from the nodular zone, and this early degeneration was associated with selective dysregulation of ion channel transcripts and altered Purkinje neuron spiking. Efforts to understand the basis for selective dysregulation of channel transcripts revealed modestly increased expression of the ATXN1 corepressor Capicua (Cic) in anterior cerebellar Purkinje neurons. Importantly, lentiviral overexpression of Cic in the nodular zone accelerated both aberrant Purkinje neuron spiking and neurodegeneration. These findings reinforce the central role for Cic in SCA1 cerebellar pathophysiology and suggest that only modest reductions in Cic are needed to have profound therapeutic impact in SCA1. Figure 3. Regionally-dysregulated ion channel genes form a functional module critical for Purkinje neuron pacemaking (A) The distribution of regularly firing, irregularly firing, and non-firing cells was recorded for Purkinje neurons in the anterior cerebellum and nodular zone. (B) Representative trace from a tonic firing wild-type and non-firing ATXN1[82Q] Purkinje neuron in the anterior cerebellum at P35. (C) Representative trace from wild-type and ATXN1[82Q] Purkinje neurons in the nodular zone at P35. (D) Quantification of the afterhyperpolarization (AHP) and ISI of wild-type and ATXN1[82Q] Purkinje neurons in the anterior cerebellum at P35. (E) Similar to (D), quantification of the AHP and ISI of wild-type and ATXN1[82Q] Purkinje neurons in the nodular zone at P35. (F) Representative traces of wild-type Purkinje neurons in the anterior cerebellum at P35. Traces are shown at baseline (left), after perfusion of 200 nM iberiotoxin (middle), and after perfusion of 200 nM iberiotoxin + 4 µM mibefradil. (G and H) Summary distribution of regularly firing, irregularly firing, and non-firing Purkinje neurons before and after perfusion of 200 nM iberiotoxin (G) and after 200 nM iberiotoxin + 4 µM mibefradil (H). ** denotes p<0.01; *** denotes p<0.001; ns denotes p>0.05; Chi-square test (A, G, H); two-way repeated measures ANOVA with Holm-Sidak correction for multiple comparisons (D, E). Supplementary Figure 3. Spontaneous Purkinje neuron firing in ATXN1[82Q] mice and wild-type controls Patch clamp electrophysiology in acute cerebellar slices from ATXN1[82Q] mice and wild-type controls was performed at P35. (A) Firing frequency in anterior cerebellum and the nodular zone is shown. (B) Coefficient of variation (CV) of the interspike interval (ISI) is shown for Purkinje neurons in the anterior cerebellum and nodular zone. ns denotes p>0.05; two-tailed Student's t-test.

show abstract

The DYT6 Dystonia Protein THAP1 Regulates Myelination within the Oligodendrocyte Lineage

Cited by 51 publications

References 50 publications

Diverse Mechanisms Lead to Common Dysfunction of Striatal Cholinergic Interneurons in Distinct Genetic Mouse Models of Dystonia

Diverse Mechanisms Lead to Common Dysfunction of Striatal Cholinergic Interneurons in Distinct Genetic Mouse Models of Dystonia

Unraveling Molecular Mechanisms of THAP1 Missense Mutations in DYT6 Dystonia

Altered Capicua expression drives regional Purkinje neuron vulnerability through ion channel gene dysregulation in Spinocerebellar ataxia type 1

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